Andrea L Hevener1, 6, Weimin He1, 6, Yaacov Barak3, 4, 6, Jamie Le1, Gautam Bandyopadhyay1, Peter Olson2, 4, Jason Wilkes1, Ronald M Evans4, 5
& Jerrold Olefsky1
1
Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California 92093, USA.
2
Department of Biology, University of California, San Diego, La Jolla, California 92093, USA.
3
Jackson Laboratory, Bar Harbor, Maine 04609, USA.
4
Gene Expression Laboratory, The Salk Institute, La Jolla, California 92093, USA.
5
Howard Hughes Medical Institute, The Salk Institute, La Jolla, California 92093, USA.
Thiazolidinediones (TZDs) are insulin-sensitizing drugs and are potent agonists of the nuclear peroxisome proliferator-activated receptor- (PPAR-). Although muscle is the major organ responsible for insulin-stimulated glucose disposal, PPAR- is more highly expressed in adipose tissue than in muscle. To address this issue, we used the Cre-loxP system to knock out Pparg, the gene encoding PPAR-, in mouse skeletal muscle. As early as 4 months of age, mice with targeted disruption of PPAR- in muscle showed glucose intolerance and progressive insulin resistance. Using the hyperinsulinemic-euglycemic clamp technique, the in vivo insulin-stimulated glucose disposal rate (IS-GDR) was reduced by 80% and was unchanged by 3 weeks of TZD treatment. These effects reveal a crucial role for muscle PPAR- in the maintenance of skeletal muscle insulin action, the etiology of insulin resistance and the action of TZDs.
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(PPAR-
80% and was unchanged by 3 weeks of TZD treatment. These effects reveal a crucial role for muscle PPAR-
